Klotho/FGF23 and Wnt in SHPT associated with CKD regulating miR-29a.

OBJECTIVE

Recently, the interaction between Klotho/fibroblast growth factor 23 (FGF-23) axis and Wnt signaling has been recognized to be responsible for chronic kidney disease (CKD)-associated comorbidities, including secondary hyperparathyroidism (SHPT). This study aimed to investigate the molecular mechanism of the interaction between Klotho/FGF23 axis and Wnt.

METHODS

A SHPT model was successfully established with a high-phosphorus diet plus 5/6 nephrectomy. Cell counting Kit-8 (CCK-8) assay and calcium deposit experiment were applied to detect the proliferation and calcium levels. Quantitative real-time PCR (qRT-PCR), Western blotting and immunofluorescence (IF) were used to determine the expression or location of FGF23, calcification-related factors and β-catenin after lentivirus-mediated Klotho overexpression. Luciferase reporter assay was performed to further validate the transcriptional regulation between microRNA-29a (miR-29a) and Dickkopf-1 (DDK1).

RESULTS

We found increased serum biochemical factors including parathyroid hormone (PTH), phosphorus, calcium, enhanced parathyroid calcification, and decreased expressions of Klotho in a rat model of secondary hyperparathyroidism. Moreover, genetic-induced upregulation of Klotho inhibited the proliferation, reduced the calcification and the alkaline phosphatase (ALP) activity, and downregulated Wnt/β-catenin signaling in parathyroid cells.

CONCLUSIONS

Mechanistically, Klotho suppressed miR-29a expression, led to upregulated expression of Wnt/β-catenin signaling inhibitor DKK1, and finally downregulated the activity of Wnt/β-catenin signaling. These findings suggest a novel molecular mechanism in the pathogenesis of CKD-associated SHPT, which provides a potential therapeutic target in the future.